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US9737566B2 - Chemotherapeutic drug combination - Google Patents
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US9737566B2 - Chemotherapeutic drug combination - Google Patents

Chemotherapeutic drug combination Download PDF

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Publication number
US9737566B2
US9737566B2 US15/114,854 US201515114854A US9737566B2 US 9737566 B2 US9737566 B2 US 9737566B2 US 201515114854 A US201515114854 A US 201515114854A US 9737566 B2 US9737566 B2 US 9737566B2
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cancer
drug combination
cells
schiff base
tumor
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US20160346325A1 (en
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Fikrettin Sahin
Aysegül DOGAN
Selami Demirci
Nese BASAK
Bulent DEDE
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Yeditepe Universitesi
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Yeditepe Universitesi
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Assigned to YEDITEPE UNIVERSITESI reassignment YEDITEPE UNIVERSITESI ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SAHIN, FIKRETTIN, BASAK, Nese, DEDE, BULENT, DEMIRCI, Selami, DOGAN, Aysegül
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/32—Manganese; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02—Polyalkylene oxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a chemotherapeutic drug combination containing heterodimic tear Cu(II)-Mn(II) complex.
  • cytotoxic and antineoplastic drugs are systemically used in chemotherapy treatment for cancer treatment.
  • Paclitaxel, doxonibicin and cisplatin are some of the most known of these drugs. Although they have many side effects, antineoplastic effects thereof are determined in many studies.
  • the chemotherapeutic drugs, which are cited in the literature and are used, do not exhibit full effect and additionally have a considerable number of side effects. Particularly cells which divide rapidly such as hair follicle or intestinal mucosa cells are affected by chemotherapeutic drugs. Suppression of immune system and the gastrointestinal problems constitute the main side effects that are observed.
  • Schiff base Compounds, which are formed as a result of condensation of aldehydes and ketones with primary amines under suitable reaction conditions, and which include C ⁇ N in their structure, are defined as Schiff base. It was demonstrated with the previous studies that Schiff bases, which can be used as catalysts in oxidation and reduction reactions, have anti-fungal and anti-bacterial effects and can be used as anti-microbial agents.
  • One of the most important targets of the pharmacological studies is to develop new molecular agents which have anti-tumoral activity. This encourages inorganic and organometallic chemistry to develop new metal-containing drugs that may be effective against cancer.
  • Pluronic block copolymers which are also known as poloxamers can be used for drug, growth factor and gene transport.
  • the polymers are comprised of hydrophilic polyethyleneoxide and hydrophobic polypropyleneoxide units. Different numbers of ethylene oxide and propylene oxide monomers enable to obtain different pluronics. Each plutonic copolymer has different, biological effects. Since they are capable of forming micelle in liquid solutions, they can easily transport the drugs into the cells.
  • US20130065864 discloses a combination containing iridium and/or rhodium for use in cancer treatment.
  • EP2407164A1 discloses an anti-cancer complex which contains Cu-II compound and which can be in the form of a complex with different components.
  • the objective of the present invention is t′ wide a drug combination that can be used actively in chemotherapy.
  • Another objective of the present invention is to provide an anticarcinogenic drug combination with no side effects.
  • a further objective of the present invention is to provide drug combination which facilitates penetration into the cells.
  • Another objective of the present invention is to provide a drug combination which shows selectivity only for cancer cells and does not harm healthy cells.
  • Another objective of the present invention is to provide a drug combination which is not toxic for the tissues and organs in the body.
  • a farther objective of the present invention is to provide a drug combination which can be easily prepared.
  • Another objective of the present invention is to provide a drug combination which enables a definitive and fast treatment.
  • a further objective of the present invention is to provide a drug combination which does not cause known chemotherapeutic side effects such as gastrointestinal system disorders such as mouth ulcers, taste changes, irritation in the inner lining of the bowel, diarrhea, appetite problems and nausea; anemia, hemorrhage, fall in blood counts, fatigue, hair loss, nervous system disorders, pain, reproductive system disorders, disorders that may occur on the skin and nails.
  • chemotherapeutic side effects such as gastrointestinal system disorders such as mouth ulcers, taste changes, irritation in the inner lining of the bowel, diarrhea, appetite problems and nausea; anemia, hemorrhage, fall in blood counts, fatigue, hair loss, nervous system disorders, pain, reproductive system disorders, disorders that may occur on the skin and nails.
  • FIG. 3 is the toxicity observed after application of 1 mg/kg of the drug combination.
  • A Liver tissue focal necrosis.
  • B Kidney tissue lymphatic infiltration,
  • C Hydrophobic degeneration in kidney tubular tissue, ling/kg drug combination.
  • FIG. 4 is the representation of the tumor formation at the dorsum after 20 ⁇ 10 6 TRAMP cell injection.
  • FIG. 5 is the hepatic portal field focus of inflammation. It is the toxicity observed in the liver following the thug administration.
  • a new chemotherapeutic drug is developed by combining a chemical molecule, which is Schiff-base derivative, with a block copolymer, which specifically recognizes cancer cells and speeds up penetration of the drug.
  • a chemical molecule which is Schiff-base derivative
  • a block copolymer which specifically recognizes cancer cells and speeds up penetration of the drug.
  • Schiff-base is used as the active molecule group.
  • pluronic P85 polymer which facilitates penetration of the drug into the cell, is used.
  • Polynuclear Schiff (heterodinuclear Cu (II)-Mn(II) complex) base complex is used as the chemical molecule in preparation of the chemotherapeutic drug formulation. This complex was used in combination with pluronics. The combination was prepared at different concentrations in in vitro and in vivo conditions and applied in the experiments. The Schiff base solution and pluronic solution, which were prepared separately for the experimental studies, were used in combination.
  • the prepared Schiff base solution was used either in PBS or cell culture medium or by injecting to animals at concentrations in the range of 0.0001-10 ⁇ g ml for in vitro conditions and at concentrations in the range of 0.001 mg/kg-10 mg/kg for in vivo conditions.
  • Toxic effect of the prepared chemicals was determined by analyzing cell viability using the MTS method (Yalvac et al., 2009).
  • the drug combination was prepared at concentrations of 5 ⁇ M, 2 ⁇ M, 1 ⁇ M, 0.5 ⁇ M and was applied on the cancer cells which were counted and seeded on 96-well culture plates (5000 cells/Well).
  • Toxicity response was determined by measuring cell viability for 3 days, formazan crystals are formed in MTS substance applied cells as a result of mitochondrial dehydrogenase enzyme activity as an indicator of cell viability. The color change was evaluated by measuring absorbance by ELISA device. The obtained values were analyzed using Microsoft Office Excel database.
  • in vivo toxicology analyses were performed in order to observe the effects of the drug formulation in the system of a living organism system.
  • Acute toxicological analyses were performed as previously stated in the literature (Uckun et al, 2002). The prepared formulation was first tried on prostate cancer. Toxicology studies were conducted on C57 mice which are used in experiments. Four different doses of 0.1 mg/kg, 0.5 mg/kg and 1 mg/kg were administered intraperitoneally to male C57 mice. 7 days later the mice were sacrificed (acute toxicology). Blood parameters and histopathological analyses were completed.
  • Visible prostate cancer tumor tissue was formed in the animals at the dorsal region by modifying the protocol which was described previously in the literature (Young et 2007). 20 ⁇ 10 6 TRAMP cells were administered to male C57 mice subcutaneously. Tumor formation process was monitored. At the end of an approximately 44 day process, the tumors became visible.
  • results obtained were statistically evaluated by one-way analysis of variance (ANOVA) using GraphPad Prism 5 software. The difference between the groups was determined by Tukey's test and p ⁇ 0.05 was considered statistically significant.
  • TRAMP Mae prostate cancer cells
  • L929 Mae fibroblast cells
  • the drug combination was applied on the cells at concentrations of 5 ⁇ M. 2 ⁇ M, 1 ⁇ M, 0.5 ⁇ M and the effects were examined at the end of three day toxicology analyses. Toxic effect was started to be observed at the end of the second day at four concentrations, and after three days of analysis, a significant amount of toxicity (at the same level with the positive control) was determined when compared with the negative control group ( FIG. 1 ).
  • Fibroblast cells were used in order to determine the toxicity of the drug combination at the same concentrations on healthy cells. Toxicity was observed at the end of three days at the two highest concentrations (5 ⁇ M and 2 ⁇ M), while no toxicity was observed at the concentrations of 1 ⁇ M and 0.5 ⁇ M ( FIG. 2 ).
  • tissue and organ weights of the animals were measured and analyses were performed to find out Whether there were any anomalies.
  • Tissue and organ samples were pathologically examined and while no toxicity was found at concentrations of 0.1 mg/kg, 0.25 mg/kg, 0.5 mg/kg, a low level of toxicity was observed at the concentration of 1 mg/kg.
  • Focal necrosis was observed in the liver tissue and hydrophobic degeneration in hepatocytes. Lymphatic infiltration was observed in the kidneys and hydrophobic degeneration in the kidney tubules ( FIG. 3 ).
  • 0.5 mg/kg was selected as the concentration to be applied in animal experiments after tumor formation.
  • Hgb (g/dL) 14.88 15.05 is an indicator of the hemoglobin values in blood.
  • MCV (fL) 51.15 51.80 is an indicator of the average size of the oxygen carrying cells.
  • MCH (pg) 19.48 19.58 is an indicator of the hemoglobin content in erythrocytes.
  • MCHC (g/dL) 39.23 38.38 is an indicator of the average hemoglobin concentration in erythrocytes.
  • RDW-SD 29.43 27.93 is an indicator of the erythrocyte distribution width.
  • Prostate tumor was formed experimentally on C57 mice in order to reproduce the clinical picture.
  • tumor formation was induced by using different numbers of cells.
  • tumors were formed by subcutaneously injecting twenty million cells to the dorsal region within a period of 30-40 days ( FIG. 4 ).
  • Prostatic adenocarcinoma formation was analyzed by using Gleason scoring. In the group to which the drug was administered, no toxicological effect was encountered except a mild congestion in the spleen. A small number of lymphocytic cells were detected around the liver central vein ( FIG. 5 ).
  • a new easily-prepared drug combination is obtained which can be actively used in chemotherapy and which is not toxic to the other tissues and organs of the body.
  • the present invention can provide a definitive and rapid treatment by enabling the drug to penetrate the cancer cells rapidly and at a large quantity.
  • Many drugs which are developed for chemotherapy have a great number of side effects. Problems such as gastrointestinal system disorders such as mouth ulcers, taste changes, irritation in the inner lining of the bowel, diarrhea, appetite problems and nausea, anemia, hemorrhage problems, fall in blood counts (damage on division of bone marrow cells), fatigue, hair loss, nervous system disorders, pain, reproductive system disorders, disorders occurring on the skin and nails are experienced following chemotherapy.
  • the drug combination of the present invention is capable of eliminating these kinds of side effects.
  • the present invention provides a treatment for the cancer types seen in human body by reducing the side effects.
  • the formulation developed within the scope of the invention can be effective on all cancer types particularly prostate cancer. It can be used for treatment of AIDS-related cancer types, breast cancer and derivatives thereof, gastrointestinal tract-related cancer types, endocrine and neuroendocrine cancers, eye cancer, genitourinary system cancer types, gynecological cancer types, prostate cancer and derivatives thereof, germ cell cancer, head and neck cancer, hematologic cancer and leukemia, musculoskeletal system cancers, neurological cancers, respiratory system and thoracic cancers, skin cancer, cancers of unknown origin, cancer types observed in childhood (acute lymphoblastic leukemia, acute myeloid leukemia), cancer types observed in women (breast, cervical, endometrial, ovarian, uterus, vaginal, vulval etc.)
  • the invention is effective in treatment and prevention of cancer types such as astrocytoma, glioma, lung cancer, hepatoma, colon cancer, osteoid cancer, pancreatic cancer skin cancer, cervical cancer, melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, anal cancer, colon carcinoma, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penial cancer, prostate cancer, urinary bladder cancer, kidney or ureter cancer, renal cell carcinoma, pelvic carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor and hypophysis adenoma.
  • cancer types such as astrocytoma, glioma, lung cancer, hepatoma, colon cancer, osteoid cancer,

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
US15/114,854 2014-01-30 2015-01-14 Chemotherapeutic drug combination Active US9737566B2 (en)

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TR201401073 2014-01-30
TR2014/01073 2014-01-30
TRA201401073 2014-01-30
PCT/TR2015/000025 WO2015116012A1 (en) 2014-01-30 2015-01-14 Chemotherapeutic drug combination

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7390832B2 (en) 2001-11-09 2008-06-24 The University Of Maryland Dinuclear copper-based compound and ligand for nucleic acid scission and anticancer treatment
CN101342142A (zh) * 2008-07-24 2009-01-14 北京大学 一种可注射的温敏原位凝胶制剂,它们的制备方法及其应用
EP2407164A1 (en) 2010-07-14 2012-01-18 Dublin Institute of Technology Intellectual Property Ltd Copper II complexes of phenanthroline and their use in cancer treatment
US20130065864A1 (en) 2010-05-22 2013-03-14 University Of Warwick Novel iridium/rhodium anti-cancer compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7390832B2 (en) 2001-11-09 2008-06-24 The University Of Maryland Dinuclear copper-based compound and ligand for nucleic acid scission and anticancer treatment
CN101342142A (zh) * 2008-07-24 2009-01-14 北京大学 一种可注射的温敏原位凝胶制剂,它们的制备方法及其应用
US20130065864A1 (en) 2010-05-22 2013-03-14 University Of Warwick Novel iridium/rhodium anti-cancer compounds
EP2407164A1 (en) 2010-07-14 2012-01-18 Dublin Institute of Technology Intellectual Property Ltd Copper II complexes of phenanthroline and their use in cancer treatment

Non-Patent Citations (19)

* Cited by examiner, † Cited by third party
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Bal et al. "Cobalt(II) and Manganese (II) complexes of Novel Schiff Bases, Synthesis, Characterization, and Thermal, Antimicrobial, Electronic, and catalytic Features", Advances in Chemistry, vol. 2014. 1-8. *
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Ren, S., Wang, R., Komatsu, K., Bonaz-Krause, P., Zyrianov, Y., McKenna, C. E., and Lien, E. J. (2002). Synthesis, biological evaluation, and quantitative structure-activity relationship analysis of new Schiff bases of hydroxysemicarbazide as potential antitumor agents. Journal of medicinal chemistry, 45(2), 410-419.
Uckun, F. M., Zheng, Y., Cetkovic-Cvrlje, M., Vassilev, A., Lisowski, E., Waurzyniak, B., Chen, C. L. (2002). In Vivo Pharmacokinetic Features, Toxicity Profile, and Chemosensitizing Activity of α-Cyano-β-hydroxy-β-methyl-N-(2, 5-dibromophenyl) propenamide (LFM-A13), a Novel Antileukemic Agent Targeting Bruton's Tyrosine Kinase. Clinical cancer research, 8(5), 1224-1233.
Yalvac, M.E., Ramazanoglu, M., Gumru, O.Z., Sahin, F., Palotás, A., Rizvanov, A.A. (2009). Comparison and optimisation of transfection of human dental follicle cells, a novel source of stem cells, with different chemical methods and electro-poration. Neurochemical research, 34(7), 1272-1277.
Young, J. G., Green, N. K., Mautner, V., Searle, P. F., Young, L. S., James, N. D. (2007). Combining gene and immunotherapy for prostate cancer. Prostate cancer and Prostate cancer and prostatic diseases, 11(2), 187-193.
Zhang et al. "Induction of tumor cell apoptosis by taurine Schiff base copper complex is associated the with inhibition of proteasomal activity". International Journal of Molecular Medicine, 22(5), 677-682. 2008. *
Zhang, X., Bi, C., Fan, Y., Cui, Q., Chen, D., Xiao, Y., and Dou, Q. R. (2008). Induction of tumor cell apoptosis by taurine Schiff base copper complex is associated with the inhibition of proteasomal activity. International journal of molecular medicine, 22(5), 677-682.

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JP2017504643A (ja) 2017-02-09
JP6416919B2 (ja) 2018-10-31
US20160346325A1 (en) 2016-12-01
EP3099309A1 (en) 2016-12-07
WO2015116012A1 (en) 2015-08-06
WO2015116012A8 (en) 2016-08-18

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